Identification of inhibitors to papillomavirus type 16 E6 protein based on three-dimensional structures of interacting proteins
Identification of inhibitors to papillomavirus type 16 E6 protein based on three-dimensional structures of interacting proteins
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DOI：
10.1016/j.antiviral.2006.03.014
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发表时间：
2006-10-01
影响因子：
7.6
通讯作者：
Androphy, Elliot J.
中科院分区：
文献类型：
--
作者：
Baleja, James D.;Cherry, Jonathan J.;Androphy, Elliot J.
人乳头瘤病毒（HPV）引起皮肤和生殖器疣。HPV类型的一个子集与进展为恶性肿瘤的高风险相关。来自高危HPV类型的E6蛋白由于其在病毒繁殖和细胞转化中的作用而代表了有吸引力的干预靶点。E6部分通过与人类细胞蛋白相互作用发挥功能，其中一些蛋白具有螺旋E6结合基序。已通过结构测定和定点诱变测试了该基序中每个氨基酸结合E6的作用。这些结构和分子生物学方法定义了与E6结合所需的官能团的空间几何结构。这种E6结合信息（E6结合药效团）被转移到一个三维查询格式，适合大型化学数据库的计算筛选。使用体外和基于细胞培养的测定法鉴定和测试化合物。几种化合物选择性地抑制E6与E6结合蛋白E6AP的相互作用，并干扰E6促进p53降解的能力。这些化合物为开发治疗乳头瘤病毒感染及其相关癌症的新药物提供了线索。(c)2006 Elsevier B.V.保留所有权利。
Human papillomaviruses (HPV) cause cutaneous and genital warts. A subset of HPV types is associated with a high-risk for progression to malignancy. The E6 protein from the high-risk HPV types represents an attractive target for intervention because of its roles in viral propagation and cellular transformation. E6 functions in part by interaction with human cellular proteins, several of which possess a helical E6-binding motif. The role for each amino acid in this motif for binding E6 has been tested through structure determination and site-directed mutagenesis. These structural and molecular biological approaches defined the spatial geometry of functional groups necessary for binding to E6. This E6-binding information (the E6-binding pharmacophore) was transferred into a three-dimensional query format suitable for computational screening of large chemical databases. Compounds were identified and tested using in vitro and cell culture-based assays. Several compounds selectively inhibited E6 interaction with the E6-binding protein E6AP and interfered with the ability of E6 to promote p53 degradation. Such compounds provide leads for the development of new pharmacologic agents to treat papillomavirus infections and their associated cancers. (c) 2006 Elsevier B.V. All rights reserved.